US4939137AExpiredUtility

Ring-fused thienopyrimidinedione derivatives

91
Assignee: ORTHO PHARMA CORPPriority: Jun 28, 1989Filed: Jun 28, 1989Granted: Jul 3, 1990
Est. expiryJun 28, 2009(expired)· nominal 20-yr term from priority
Inventors:Ronald K. RussellRichard A. Rampulla
C07D 495/16
91
PatentIndex Score
43
Cited by
2
References
18
Claims

Abstract

The synthesis of ring-fused thienopyrimidinedione derivatives is described. The novel ring-fused thienopyrimidinedione derivatives are generally vasodilating agents and antihypertensive agents and as such are useful as cardiovascular agents.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
       1. A compound of the formula ##STR8## where X is C═O or CHOR 3  or C═NOR 4  or CHNHR 3  when Y is CH 2  or X and Y together are CH═CH or Y is NH when X is C═O ##STR9## R 1  is hydrogen, halogen, nitro or C 1  -C 3  alkyl R 2  is ##STR10## R 3  is hydrogen, C 1  -C 3  alkyl or COR 5  ; R 4  is hydrogen or C 1  -C 6  alkyl;   R 5  is C 1  -C 6  alkyl, phenyl or phenyl substituted by halogen, C 1  -C 6  alkyl, C 1  -C 3  alkoxy, nitro, CF 3 , amino or C 1  -C 6  dialkylamino;   Ar is phenyl or phenyl substituted by halogen, C 1  -C 6  alkyl, C 1  -C 3  alkoxy, nitro, CF 3 , amino or C 1  -C 6  dialkylamino;   m is 1-5; and   n is 2-6   
     
     
       2. The compound of claim 1 wherein R 1  is hydrogen or C 1  -C 3  alkyl;   R 3  is hydrogen or COR 5  ;   R 4  is hydrogen or methyl;   R 5  is C 1  -C 6  alkyl or phenyl or phenyl substituted by   4-chloro or 4-methoxy;   Ar is phenyl or phenyl substituted by halogen, methyl, methoxy or CF 3  ;   m is 1-3; and   n is 2-5.   
     
     
       3. The compound of claim 1 selected from the group consisting of 3,4,5,7,8,9-hexahydro-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5,9-trione;   3,4,5,7,8,9-hexahydro-4-[2-[4-(2-methylphenyl)piperazin-1-yl]ethyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5,9-trione;   3,4,5,7,8,9-hexahydro-4-[2-(4-phenylpiperazin-1-yl)ethyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5,9-trione;   4-[2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl]-3,4,5,7,8,9-hexahydrothieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5,9-trione;   4-[2-[4-(3-chlorophenyl)piperazin-1-yl]ethyl]-3,4,5,7,8,9-hexahydrothieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5,9-trione;   3,4,5,7,8,9-hexahydro-4-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5,9-trione;   3,4,5,7,8,9-hexahydro-4-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5,9-trione;   3,4,5,7,8,9-hexahydro-4-[5-[4-(2-methoxyphenyl)piperazin-1-yl]pentyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5,9-trione;   3,4,5,7,8,9-hexahydro-2-methyl-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5,9-trione;   7,8-dihydro-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[2,3,4-de]pyrido[1,2-c]pyrimidine-3,5,9-trione;   4,7,8,9-tetrahydro-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[4,3,2-de]pyrimido[3,4-a]azepine-3,5,10-trione;   4.   
     
     
       4. 7,8,9,10,11-hexahydro-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[4,3,2-de]pyrimido[3,4-a]azocine-3,5,11-trione; 3,4,5,7,8,9-hexahydro-4-[2-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)ethyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5,9-trione;   4-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-3,4,5,7,8,9-hexahydrothieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5,9-trione;   4-[2-[4-[bis(4-fluorophenyl)methylene]piperidin-1-yl]ethyl]-3,4,5,7,8,9-hexahydrothieno[4,3,2-de]pyrimidine-3,5,9-trione;   3,4,5,7,8,9-hexahydro-9-hydroxy-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5-dione;   10-hydroxy-4,7,8,9-tetrahydro-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[4,3,2-de]pyrimido[3,4-a]azepine-3,5-dione;   3,4,5,7-tetrahydro-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5-dione;   3,4,5,7,9,10-hexahydro-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-9H-thieno[4,3,2-de]pyrimido[1,2-a]1,4]diazepine-3,5,10-trione;   
     
     
       3. 4,5,7,8,9-hexahydro-9-methoxyimino-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5-dione; 4,7,8,9-tetrahydro-10-methoxyimino-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[4,3,2-de]pyrimido[3,4-a]azepine-3,5-dione;   3,4,5,7,8,9-hexahydro-9-methoxyimino-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-2-methylthieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5-dione;   3,4,5,7,8,9-hexahydro-9-methoxyimino-4-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]thieno-[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5-dione;   9-acetyloxy-3,4,5,7,8,9-hexahydro-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[4,3,2,de]pyrido[1,2-c]pyrimidine-3,5-dione;   3,4,5,7,8,9-hexahydro-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-9-(butanoyloxy)thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5-dione;   3,4,5,7,8,9-hexahydro-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-9-(hexanoyloxy)thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5-dione;   3,4,5,7,8,9-hexahydro-9-(2-methylpropanoyloxy)-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5-dione;   9-benzoyloxy-3,4,5,7,8,9-hexahydro-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5-dione;   9-(4-chlorobenzoyloxy)-3,4,5,7,8,9-hexahydro-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5-dione;   9-amino-3,4,5,7,8,9-hexahydro-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5-dione;   9-acetylamino-3,4,5,7,8,9-hexahydro-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5-dione;   9-benzoylamino-3,4,5,7,8,9-hexahydro-4-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5-dione;   4-[4-[4-(4-fluorobenzoyl)piperidin-1-yl]butyl]-3,4,5,7,8,9-hexahydrothieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5,9-trione;   4-[5-[4-(3-trifluoromethylphenyl)piperazin-1-yl]pentyl]-3,4,5,7,8,9-hexahydrothieno[4,3,2-de]pyrido[1,2-c]pyrimidine-3,5,9-trione; and   4-[5-[4-[bis(4-fluorophenyl)methylene]piperadin-1-yl]pentyl]-3,4,5,7,8,9-he   
     
     
       xahydrothieno[4,3,2-de]pyrimidine-3,5,9-trione Monooxalate. 4. A pharmaceutical composition comprising as an active ingredient an effective amount of a compound of claim 1 and a suitable pharmaceutical carrier. 
     
     
       5. A pharmaceutical composition comprising as an active ingredient an effective amount of a compound of claim 2 and a suitable pharmaceutical carrier. 
     
     
       6. A pharmaceutical composition comprising as an active ingredient an effective amount of a compound of claim 3 and a suitable pharmaceutical carrier. 
     
     
       7. A process for synthesizing a compound of claim 1 wherein X is C═O and Y is CH 2  comprising cyclizing a thienopyrimidine-2,4-dione of the formula ##STR11## where ##STR12## R 1 , R 2 , m and n are as defined in claim 1, with a strong dehydrating agent. 
     
     
       8. A process for synthesizing a compound of claim 1 wherein X is C═NOR 4  and Y is CH 2  comprising mixing a ketone of the formula ##STR13## where ##STR14## R 1 , R 2 , m and n are as defined in claim 1, with a hydroxylamine, a substituted hydroxylamine or a hydroxylamine salt and optionally adding a base. 
     
     
       9. A process for synthesizing a compound of claim 1 wherein X is C═O and Y is NH comprising the use of Beckmann rearrangement conditions to expand the ring structure of an oxime of the formula ##STR15## where ##STR16## R 1 , R 2 , m and n are as defined in claim 1 to the desired compound of the formula ##STR17## where ##STR18## R 1 , R 2 , m and n are as defined above. 
     
     
       10. A process for synthesizing a compound of claim 1 wherein X is CHOR 3  and Y is CH 2  comprising the steps of (a) reducing a ketone of the formula ##STR19##  where ##STR20##  R 1 , R 2 , m and n are as defined in claim 1, with a hydride reagent, to produce an alcohol of the formula ##STR21##  where ##STR22##  R 1 , R 2 , m and n are as defined above; and (b) optionally alkylating the alcohol with an alkyl halide in an inert solvent in the presence of a base to produce an alkylated compound of the formula ##STR23##  where ##STR24##  R 1 , R 2 , m and n are as defined above and R 3  is C 1  -C 3  alkyl or COR 5 , wherein R 5  is as defined in claim 1.   
     
     
       11. A process for synthesizing a compound of claim 1 wherein X and Y together are CH═CH comprising dehydrating an alcohol of the formula ##STR25##  where ##STR26##  R 1 , R 2 , m and n are as defined in claim 1, with a strong acid, acetic acid/acetic anhydride or methanesulfonyl chloride/triethylamine in dichloromethane. 
     
     
       12. A process for synthesizing a compound of claim 1 wherein X is CHNHR 3  and Y is CH 2  comprising the steps of (a) mixing a ketone of the formula ##STR27##  where ##STR28##  R 1 , R 2 , m and n are as defined in claim 1, with a substituted hydroxylamine to produce an oxime of the formula ##STR29##  where ##STR30##  R 1 , R 2 , m and n are as defined above and R 4  is C 1  -C 6  alkyl;   (b) reducing the oxime with a hydride reagent to produce an amine of the formula ##STR31##  where ##STR32##  R 1 , R 2 , m and n are as defined above; and (c) optionally alkylating the amine with an alkyl halide in an inert solvent in the presence of a base to produce an alkylated amine of the formula ##STR33##  where ##STR34##  R 1 , R 2 , m and n are as defined above and R 3  is C 1  -C 3  alkyl; or   (d) optionally mixing the amine with an acid halide in an inert solvent to produce an amide of the formula ##STR35##  where ##STR36##  R 1 , R 2 , m and n are as defined above and R 5  is as defined in claim 1.   
     
     
       13. A method of treating hypertension in mammals by administering an effective amount of a compound of claim 1. 
     
     
       14. A method of treating hypertension in mammals by administering an effective amount of a compound of claim 2. 
     
     
       15. A method of treating hypertension in mammals by administering an effective amount of a compound of claim 3. 
     
     
       16. A method of treating cardiovascular disease in mammals by administering an effective amount of a compound of claim 1. 
     
     
       17. A method of treating cardiovascular disease in mammals by administering an effective amount of a compound of claim 2. 
     
     
       18. A method of treating cardiovascular disease in mammals by administering an effective amount of a compound of claim 3.

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